ABSTRACT Chondrocyte-pericellular matrix derived signaling maintains tissue integrity in the temporomandibular joint Temporomandibular disorders affect 3-7% of the population. TMJ condylar cartilage integrity is central to TMJ health and many TMDs are associated with its degeneration. The pathophysiology of degenerative joint disease (DJD) in the TMJ is ill-defined and contemporary molecular targets for clinical intervention have yet to be determined. Chondrocyte-pericellular matrix derived signaling is a known regulator of cartilage homeostasis and it represents a promising potential therapeutic target for DJD. The major component of the pericellular matrix in the TMJ is type VI collagen. Nerve/glial antigen 2 (NG2) is a known receptor of type VI collagen, but NG2-type VI collagen interactions have not been studied in detail in mandibular condylar cartilage. In other cell types, the NG2-pericellular matrix interactions are a critical regulator of cell proliferation, differentiation, migration, and viability. Our preliminary data illustrate that a) NG2 colocalizes with type VI collagen in healthy articular chondrocytes in the TMJ, b) that this colocalization is disrupted during degeneration, c) that degenerative changes are associated with high levels of internalized NG2, d) and that internalized NG2 is closely associated with a marker for oxidative stress, OMI/HtrA2. We hypothesize that cartilage degeneration in TMJ DJD is mediated, in part, by proteolytic cleavage of the NG2 ectodomain, activation, and internalization to regulate oxidative stress through OMI/Htra2 pathway. We will test this hypothesis with two specific aims. In aim 1, we will implicate ectodomain proteolysis in NG2 activation and internalization by linking cartilage degeneration with NG2 internalization and measured protease levels in wild-type and protease knockout mice and cells. In aim 2, we will define the functionality of NG2 as a mediator of oxidative stress by linking cartilage degeneration with markers of oxidative stress, ER stress, and autophagy in wild-type and NG2 knockout mice and cells. Together, these aims define and evaluate an entirely novel molecular mechanism of chondrocyte function that is contextually linked to mechanical and metabolic oxidative stresses known to cause TMDs. Long term, we seek to use these data to solve clinical problems associated with defining precise methods of TMD classification, prevention, and treatment.